Christian Vogelberg

Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma.

Asthma is caused by a combination of poorly understood genetic and environmental factors. We have systematically mapped the effects of single nucleotide polymorphisms (SNPs) on the presence of childhood onset asthma by genome-wide association. We characterized more than 317,000 SNPs in DNA from 994 patients with childhood onset asthma and 1,243 non-asthmatics, using family and case-referent panels. Here we show multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P value of P < 10-12. In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in Epstein–Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (P < 10-22) in cis with transcript levels of ORMDL3, a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum. The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.

Filaggrin mutations, atopic eczema, hay fever, and asthma in children

BACKGROUND Mutations in the filaggrin gene (FLG) have been shown to play a significant role in ichthyosis vulgaris and eczema, 2 common chronic skin diseases. However, their role in the development of other atopic diseases such as asthma and rhinitis has not yet been clarified in large population-based studies. OBJECTIVES To study the effect of FLG mutations at the population level and their effect on other atopic phenotypes. METHODS Association analysis of the 2 common FLG-null mutations R501X and 2282del4 and 3 recently identified rare FLG variants (R2447X, S3247X, 3702delG) was performed on our cross-sectional population of German children (n = 3099) recruited as part of the International Study of Asthma and Allergies in Childhood II in Munich (n = 1159) and Dresden (n = 1940). RESULTS FLG variants increased the risk for eczema more than 3-fold (odds ratio [OR], 3.12; 95% CI, 2.33-4.173; P = 2.5 x 10(-14); population-attributable risk, 13.5%). Independent of eczema, FLG mutations conferred a substantial risk for allergic rhinitis (OR, 2.64; 95% CI, 1.76-4.00; P = 2.5 x 10(-6); population-attributable risk, 10.8%). Nasal biopsies demonstrated strong filaggrin expression in the cornified epithelium of the nasal vestibular lining, but not the transitional and respiratory nasal epithelia. In contrast, the association with asthma (OR, 1.79; 95% CI, 1.19-2.68; P = .0048) was restricted to asthma occurring in the context of eczema, and there was a strong association with the complex phenotype eczema plus asthma (OR, 3.49; 95% CI, 2.00-6.08; P = 1.0 x 10(-5)). CONCLUSION Our results suggest that FLG mutations are key organ specific factors predominantly affecting the development of eczema and confer significant risks of allergic sensitization and allergic rhinitis as well as asthma in the context of eczema.

Toll-like receptor heterodimer variants protect from childhood asthma

BACKGROUND Early exposure to microbes reduces the risk for asthma. Toll-like receptors (TLRs) represent a major group of receptors for the specific recognition of pathogen-associated molecular patterns of microbes capable of activating innate and adaptive immunity. OBJECTIVE Because TLRs can influence key events in the induction and perpetuation of asthma and atopy, we sought to determine whether genetic alterations in TLR genes affect asthma risk. METHODS We systematically evaluated putatively functional genetic variants in all 10 human TLR genes for their association with different asthma phenotypes in a case-control study (n = 1872) by using matrix-assisted laser desorption/ionization time-of-flight genotyping. For polymorphisms showing association with atopic asthma, effects on gene and protein expression were studied by means of RT-PCR and flow cytometry ex vivo. T-cell cytokine production was evaluated by means of ELISA after stimulation of the respective TLRs with specific ligands. RESULTS Protective effects on atopic asthma were identified for single nucleotide polymorphisms in TLR1 (odds ratio [OR], 0.54; 95% CI, 0.37-0.81; P = .002), TLR6 (OR, 0.54; 95% CI, 0.37-0.79; P = .003), and TLR10 (OR, 0.58; 95% CI, 0.39-0.86; P = .006), all capable of forming heterodimers with TLR2. Effects remained significant after correction for multiple comparisons. PBMCs of minor allele carriers showed increased levels of the respective TLR mRNA and proteins, augmented inflammatory responses, increased T(H)1 cytokine expression, and reduced T(H)2-associated IL-4 production after specific stimulation. CONCLUSION These results suggest that functional relevant TLR1 and TLR6 variants are directly involved in asthma development.

Unifying Candidate Gene and GWAS Approaches in Asthma

The first genome wide association study (GWAS) for childhood asthma identified a novel major susceptibility locus on chromosome 17q21 harboring the ORMDL3 gene, but the role of previous asthma candidate genes was not specifically analyzed in this GWAS. We systematically identified 89 SNPs in 14 candidate genes previously associated with asthma in >3 independent study populations. We re-genotyped 39 SNPs in these genes not covered by GWAS performed in 703 asthmatics and 658 reference children. Genotyping data were compared to imputation data derived from Illumina HumanHap300 chip genotyping. Results were combined to analyze 566 SNPs covering all 14 candidate gene loci. Genotyped polymorphisms in ADAM33, GSTP1 and VDR showed effects with p-values <0.0035 (corrected for multiple testing). Combining genotyping and imputation, polymorphisms in DPP10, EDN1, IL12B, IL13, IL4, IL4R and TNF showed associations at a significance level between p = 0.05 and p = 0.0035. These data indicate that (a) GWAS coverage is insufficient for many asthma candidate genes, (b) imputation based on these data is reliable but incomplete, and (c) SNPs in three previously identified asthma candidate genes replicate in our GWAS population with significance after correction for multiple testing in 14 genes.

The role of polymorphisms in ADAM33, a disintegrin and metalloprotease 33, in childhood asthma and lung function in two German populations

BackgroundADAM33, the first asthma candidate gene identified by positional cloning, may be associated with childhood asthma, lung function decline and bronchial hyperresponsiveness. However, replication results have been inconclusive in smaller previous study populations probably due to inconsistencies in asthma phenotypes or yet unknown environmental influences. Thus, we tried to further elucidate the role of ADAM33 polymorphisms (SNPs) in a genetic analysis of German case control and longitudinal populations.MethodsUsing MALDI-TOF, ten ADAM33 SNPs were genotyped in 1,872 children from the International Study of Asthma and Allergy in Childhood (ISAAC II) in a case control setting and further 824 children from the longitudinal cohort Multicentre Study of Allergy (MAS). In both populations the effects of single SNPs and haplotypes were studied and a gene environment analysis with passive smoke exposure was performed using SAS/Genetics.ResultsNo single SNP showed a significant association with doctors diagnosis of asthma. A trend for somewhat more profound effects of ADAM33 SNPs was observed in individuals with asthma and BHR. Haplotype analyses suggested a minor effect of the ADAM33 haplotype H4 on asthma (p = 0.033) but not on BHR. Associations with non atopic asthma and baseline lung function were identified but no interaction with passive smoke exposure could be detected.ConclusionThe originally reported association between ADAM33 polymorphisms and asthma and BHR could not be confirmed. However, our data may suggest a complex role of ADAM33 polymorphisms in asthma ethiology, especially in non atopic asthma.

Prediction of the incidence, recurrence, and persistence of atopic dermatitis in adolescence: a prospective cohort study.

BACKGROUND Although it is known that atopic dermatitis (AD) can develop during adolescence, research on its course and predictors in this age group is thus far limited. OBJECTIVE We aimed to describe the course of AD over puberty and prospectively determine risk factors for the incidence, recurrence, and persistence of AD until adolescence in a population-based cohort study. METHODS German participants of the International Study of Asthma and Allergies in Childhood Phase II were followed prospectively. The final dataset comprised 2857 adolescents, of whom 2433 were unaffected by AD at baseline. Bivariate and multivariate prediction models for the incidence, recurrence, and persistence of AD using early-life factors, family history of atopic diseases, and job history as predictors were developed. RESULTS The incidence of AD between ages 9 to 11 and 16 to 20 years was 1.7%, and recurrence was 2.4%. AD persisted in 47.6% of adolescents with AD symptoms at baseline (n = 424). High socioeconomic status, female sex, asthma symptoms and a positive skin prick test response at baseline, parental history of rhinitis/AD, and having worked in a high-risk job were significant predictors for the course of disease. With all the factors present, the probability of the incidence of AD was 21.4% (95% CI, 1.8% to 80.2%) and increased up to 81.7% (95% CI, 47.0% to 95.8%) for recurrence of AD and 87.6% (95% CI, 63.4% to 96.6%) for persistence of AD among those affected by AD. Early-life exposures did not predict the course of AD over puberty. CONCLUSION Genetic factors, early allergen sensitization, and having worked in a high-risk job seem to be more important for disease development in late adolescence than other early-life exposures.

MMP-9 gene variants increase the risk for non-atopic asthma in children

BackgroundAtopic and non-atopic wheezing may be caused by different etiologies: while eosinophils are more important in atopic asthmatic wheezers, neutrophils are predominantly found in BAL samples of young children with wheezing. Both neutrophils as well as eosinophils may secrete matrix metalloproteinase 9 (MMP-9). Considering that MMP-9 plays an important role in airway wall thickening and airway inflammation, it may influence the development of obstructive airway phenotypes in children. In the present study we investigated whether genetic variations in MMP-9 influence the development of different forms of childhood asthma.MethodsGenotyping of four HapMap derived tagging SNPs in the MMP-9 gene was performed using MALDI-TOF MS in three cross sectional study populations of German children (age 9-11; N = 4,264) phenotyped for asthma and atopic diseases according to ISAAC standard procedures. Effects of single SNPs and haplotypes were studied using SAS 9.1.3 and Haploview.ResultsSNP rs2664538 significantly increased the risk for non-atopic wheezing (OR 2.12, 95%CI 1.40-3.21, p < 0.001) and non-atopic asthma (OR 1.66, 95%CI 1.12-2.46, p = 0.011). Furthermore, the minor allele of rs3918241 may be associated with decreased expiratory flow measurements in non-atopic children. No significant effects on the development of atopy or total serum IgE levels were observed.ConclusionsOur results have shown that homozygocity for MMP-9 variants increase the risk to develop non-atopic forms of asthma and wheezing, which may be explained by a functional role of MMP-9 in airway remodeling. These results suggest that different wheezing disorders in childhood are affected differently by genetic alterations.

Prediction of the incidence and persistence of allergic rhinitis in adolescence: A prospective cohort study

BACKGROUND Predictive models have rarely been used in allergy research and practice. However, they might support physicians in advising patients. OBJECTIVE The aim of this study was to create predictive models for the incidence and persistence of allergic rhinitis (AR) during adolescence. METHODS A prospective population-based cohort study was conducted starting at age 9 to 11 years. Potential risk factors for atopic diseases obtained at baseline in 2810 subjects were used to create predictive logistic regression models for the incidence and persistence of physician-diagnosed AR with current symptoms at age 15 to 18 years. RESULTS Positive skin prick test responses to outdoor allergens at baseline were the most important determinant for both the incidence and persistence of AR until follow-up. For the incidence of AR, positive skin prick test responses to indoor allergens, parental history of asthma, female sex, and not having been breast-fed exclusively for 2 or more months were additional statistically significant independent risk factors. Depending on the number of risk factors present, the probability of the incidence of AR increased from 2% (no risk factors present) to 72% (full model; 95% CI, 58% to 85%). The probability of persistence of AR ranged from 33% (no risk factors present) to 83% (full model; 95% CI, 70% to 97%). CONCLUSION The course of AR over puberty can be predicted using risk factors that are easy to determine in childhood. Sensitization to outdoor allergens seems to play a much greater role for disease development than sensitization to indoor allergens. This might help pediatricians in advising patients.

Rare TLR2 mutations reduce TLR2 receptor function and can increase atopy risk.

Background:  Common genetic variations in toll‐like receptor 2 (TLR2), an innate pathogen recognition receptor, may influence the development of atopic diseases. So far, very little is known about the role of rare TLR2 mutations in these diseases.

S3-Leitlinie Allergieprävention - Update 2014 Leitlinie der Deutschen Gesellschaft für Allergologie und klinische Immunologie (DGAKI) und der Deutschen Gesellschaft für Kinder- und Jugendmedizin (DGKJ)

ZusammenfassungDie weiterhin hohe Prävalenz allergischer Erkrankungen in westlichen Industrienationen und die eingeschränkten Möglichkeiten einer kausalen Therapie machen eine evidenzbasierte Primärprävention notwendig. Die Empfehlungen der zuletzt 2009 veröffentlichten S3-Leitlinie Allergieprävention wurden auf der Basis einer aktuellen systematischen Literatursuche überarbeitet und konsentiert.Die Evidenzsuche erfolgte für den Zeitraum Mai 2008 bis Mai 2013 in den elektronischen Datenbanken Cochrane und MEDLINE sowie in den Referenzlisten aktueller Übersichtsarbeiten und durch Expertenanschreiben. Die aufgefundene Literatur wurde in zwei Filterprozessen zunächst nach Titel und Zusammenfassung und die verbliebenen Arbeiten im Volltext auf Relevanz hin überprüft. Für eingeschlossene Studien wurden Evidenzgrade vergeben und die Studienqualität im Sinne des Verzerrungspotenzials (niedrig/hoch) angegeben. Die überarbeiteten Empfehlungen wurden unter Beteiligung von Vertretern relevanter Fachgesellschaften und (Selbsthilfe-)Organisationen formal konsentiert (nominaler Gruppenprozess).Von 3.284 Nennungen wurden 165 Studien (eine Metaanalyse, 15 „systematic reviews“, 31 randomisierte kontrollierte Studien, 65 Kohortenstudien, zwölf Fall-Kontroll-Studien und 41 Querschnittstudien) eingeschlossen und bewertet. Im Wesentlichen unverändert blieben die Empfehlungen zum Vollstillen über vier Monate aus Gründen der Allergieprävention (bei Risikokindern alternativ hypoallergene Säuglingsnahrung), der Vermeidung von Übergewicht, zum Fischkonsum (in Schwangerschaft/Stillzeit und als Beikost), zur Vermeidung der Luftschadstoff- und Tabakrauchexposition, der Vermeidung eines schimmelpilzfördernden Innenraumklimas und der Impfung nach Empfehlungen der Ständigen Impfkommission (STIKO). Unverändert bleibt auch die Aussage, dass eine Reduktion des Hausstaubmilbenallergengehalts als primärpräventive Maßnahme nicht empfohlen wird. Die Beikosteinführung sollte nicht verzögert werden. Bei Risikokindern sollten keine Katzen angeschafft werden. Die Haltung von Hunden im Haushalt ist nicht mit einem erhöhten Allergierisiko verbunden. Neu aufgenommen wurde die Empfehlung, das erhöhte Asthmarisiko nach Kaiserschnittentbindung zu berücksichtigen. Weitere Stellungnahmen wurden zu Prä- und Probiotika, psychosozialen Faktoren, Medikamenten und verschiedenen Nahrungsbestandteilen formuliert.Die Überarbeitung der Leitlinie auf einer umfangreichen Evidenzgrundlage führte sowohl zu einer Bestätigung bestehender Empfehlungen als auch zu Modifikationen und neuen Empfehlungen. Die Aktualisierung der Leitlinie ermöglicht es, evidenzbasierte und aktuelle Präventionsempfehlungen zu geben.